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Introduction: Myrica nagi Thunb. (family Myricaceae) are actinorhizal plants showing symbiotic interaction with Frankia. Inhibition of cyclooxygenase-2 (COX-2) enzyme is known to be significant in preventing inflammation and in therapeutics. Objectives: Our principal focus was to identify COX-2 enzyme inhibitors, safer and natural anti-inflammatory compounds from M. nagi. Protein–ligand interaction has a significant role in structure-based drug design. Materials and Methods: Sixty-eight phytochemicals were therefore screened and evaluated for their binding energies with COX-2. These phytoconstituents were screened and analyzed for drug Likeliness along with Lipinski's rule of five. The X-ray crystallographic structure of the target COX-2 (protein data bank [PDB] ID: 4PH9), obtained from PDB, was docked with PubChem structures of phytochemicals using AutoDock 4.2 that uses Lamarckian genetic algorithm. Further, myricetin was subjected to in vitro anti-inflammatory assay using RAW-264.7 cell lines and inhibitory concentration (IC50) value was also determined. Results: The myricetin, myricitrin, and corchoionoside-C inhibited COX-2 with − 6.52, −4.94, and − 4.94 Kcal/mol binding energies, respectively, comparable to ibuprofen. Eventually, bioactivity score and absorption distribution metabolism excretion-toxicity properties showed considerable biological activities as G protein-coupled receptor, nuclear receptor, protease inhibitor, and enzyme inhibitors for myricetin, myricitrin, and corchoionoside-C phytochemicals. Molecular docking revealed hydrophobic interactions followed by four, nine, and four numbers of hydrogen bonds between myricetin, myricitrin, and corchoionoside-C, respectively, within the binding site of COX-2. Flavonol myricetin showed 112 μg/mL as IC50 value when it was subjected to in vitro cytotoxicity assay. These results clearly demonstrated that myricetin, myricitrin, and corchoionoside-C could act as highly potential COX-2 inhibitors. Therefore, in silico and in vitro studies revealed that of three best phytochemicals, myricetin could be promising candidate. [ABSTRACT FROM AUTHOR]

The present work describes the design and synthesis of novel series of ten pyrazolo[3,4- d ]pyrazolo derivatives. Four compounds 3a , 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. They are even more potent than non-sterodial anti-inflammatory drug cyclooxygenase inhibitor diclofenac sodium. Our best hit 4d appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. The in silico findings come in line with the in vitro and in vivo assay results and also suggest that these compounds have the potetntial to be COX-2 selective inhibitors since they have typical binding modes of the benchmark drug celecoxib. • Design and synthesis of novel series of pyrazolo[3,4- d ]pyrazolo derivatives. • The best hit, 4d with COX-1 IC 50 of 28 µM and COX-2 IC 50 of 23 µM. • 4d adopt similar binding modes to the standard COX-2 inhibitor, celecoxib. • 3a , 3d , 4d and 4f exhibited anti-inflammatory activity that was comparable to celecoxib. In this study, the acid chlorides of pyrazolo[3,4- d ]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC 50 of 26 µM and a COX-2 IC 50 of 34 µM, 3b had a COX-1 IC 50 of 19 µM and a COX-2 IC 50 of 31 µM, 3a had a COX-2 IC 50 of 42 µM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues. Our best hit, 4d (COX-1 IC 50 of 28 µM, COX-2 IC 50 of 23 µM), appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. Additionally, the resultant novel compounds were tested in several in vivo assays. Four compounds 3a (COX-2 IC 50 of 42 µM), 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available COX-2 inhibitor celecoxib. Interestingly, they showed greater potency than the famous non-steroidal anti-inflammatory drug, Diclofenac sodium. In summary, these novel pyrazolo[3,4- d ]pyrimidine analogues showed interesting anti-inflammatory activity and could act as a starting point for future drugs. [ABSTRACT FROM AUTHOR]

COX-2 is a widely studied biological target, since its activity is directly related to the inflammation response. The design of COX-2 selective inhibitors is an ongoing topic in drug design. We performed a quantitative structure–activity relationship and docking studies over a series of benzenesulfonamide derivatives on their inhibition towards COX-1 and COX-2, in order to rationalize their selectivity towards COX-2. Constitutional, topological and molecular property descriptors for the QSAR models and molecular docking calculations were employed. The mathematical model highlighted that lipophilic character and size are the most important features for COX-2 inhibition by benzenesulfonamides. A second QSAR model revealed that the dipole moment, the number of hydrogen bond donors and lipophilicity descriptors of benzenesulfonamides are crucial for their binding to COX-1. Moreover, artificial neural networks were employed to improve the prediction power of the COX-1 inhibition QSAR model. In this sense, we proposed new selective potential inhibitors by introducing different halogens into the benzenesulfonamide scaffold, improving their interactions with key residues of COX-2. [ABSTRACT FROM AUTHOR]

A series of 2-(4-substitutedmethylphenyl)propionic acid derivatives(6a–6m)were synthesized, characterized and evaluated for cyclooxygenase (COX) enzyme inhibitory and antimicrobial activity. Test compounds that exhibited good COX inhibition and antibacterial activity were further screened for their cytotoxicity and genotoxicity. Compounds6hand6lshowed better COX-1 and COX-2 inhibition when compared to ibuprofen. Inhibition potency of these compounds against COX-2 was very close to that of nimesulide. The compounds6d, 6h, 6land6mdisplayed promising antibacterial property when compared to chloramphenicol. However, the compound6lwas emerged as the best dual COX inhibitory-antibacterial agent in this study. The ADME prediction of the compounds revealed that they may have a good pharmacokinetic profile. Docking results of the compounds6hand6lwith COX-1 (PDB ID: 1EQG) also exhibited a strong binding profile. [ABSTRACT FROM PUBLISHER]

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications as analgesics and antipyretics. Currently, there is a growing interest in their antitumor activity and their ability to reduce the risk and mortality of several cancers. While several studies revealed the ability of NSAIDs to induce apoptosis and inhibit angiogenesis in cancer cells, their exact anticancer mechanism is not fully understood. However, both cyclooxygenase (COX)-dependent and -independent pathways were reported to have a role. In an attempt to develop new anticancer agents, a series of diphenylthiazole substituted thiazolidinone derivatives was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. Additionally, the inhibitory activity of the synthesized derivatives against COX enzymes was investigated as a potential mechanism for the anticancer activity. Cytotoxicity assay results showed that compounds 15b and 16b were the most potent anticancer agents with half maximal inhibitory concentrations (IC 50 ) between 8.88 and 19.25 μM against five different human cancer cell lines. Interestingly, COX inhibition assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good COX-2 inhibition comparable to that of celecoxib. Further support to our results were gained by the docking studies which suggested the ability of compound 15b to bind into COX-2 enzyme with low energy scores. Collectively, these results demonstrated the promising activity of the newly designed compounds as leads for subsequent development into potential anticancer agents. [ABSTRACT FROM AUTHOR]

Cyclooxygenase −1 (COX-1) selective inhibitors are anticipated to be potential therapeutic agents for thrombosis, tumorigenesis, atherosclerosis, neuroprotection, and oxidative stress. In this study, a 3D-QSAR pharmacophore model was developed for potent and selective COX-1 inhibition based on 44 compounds from four different scaffolds using Phase, Schrödinger. One (hydrogen-bond) acceptor, one hydrophobic, and two aromatic sites (AHRR) contribute to COX-1 inhibitory activity. Test and decoy sets were used to corroborate the best hypothesis and the validated hypothesis was used to screen the SPECS database. The resultant hits were filtered by standard precision (SP) and extra precision (XP) modes of docking using Glide, Schrödinger which yielded five hits. Free energy calculations were carried out to quantify the affinity differences of the hits towards COX enzymes. These five hits were subjected to in vitro COX (ovine) inhibitory activity studies. The hits displayed potent COX-1 inhibitory activity and good selectivity versus COX-2 enzyme. The compounds also protected the nitric oxide (NO) induced cell death mediated by COX-1 in mouse macrophages cell line. Hence, we hypothesize that these compounds could be promising leads for the design of superior COX-1 inhibitors and insights gained from further exploration of the same could provide pertinent clues for the treatment of the conditions mentioned above. [ABSTRACT FROM AUTHOR]

The various NSAID's known to the scientists till date, reduces fever and inflammation when the body gets overzealous in its defenses against infection and damage but it may slows blood flow and blood clotting, reducing the chance of stroke and heart attack in susceptible individuals. Three-dimensional structures of pharmacologically important macromolecules offer a route to the discovery of new drugs. Understanding the macromolecule-ligand interactions and validation of method used for docking and virtual screening of chemical databases is crucial step in structure-based design. We therefore carried out molecular docking for structurally diverse COX-1/COX-2 inhibitors including traditional NSAIDs and Autodock 4.1.2. The complete computational analysis has revealed the best possible ligands combinations for the selective inhibition of COX-2 and COX-1. 3-D Structure of COX-2 has been predicted using the homology modeling tools. Results of docking of bound ligands like Tenoxicam and Valdecoxib have given the best binding scores Autodock.4.1.2. Molecular docking of structurally diverse selective COX-2 and COX-1 inhibitors has been successfully carried out. [ABSTRACT FROM AUTHOR]

Abstract: Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a “lead” to design new isoxazoles (2a–m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a–m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure–activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran-2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 μM; COX-2 IC50 > 50 μM) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 μM). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. [Copyright &y& Elsevier]

Abstract: A series of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and 2-alkylsulfonyl-1H-imidazole derivatives were synthesized. All compounds were tested in human blood assay to determine COX-1 and COX-2 inhibitory potency and selectivity. Among the synthesized compounds, 2-alkylthio series were more potent and selective than 2-sulfonylalkyl derivatives. In molecular modeling, interaction of 2-sulfonylalkyl moiety with Arg120 in COX-1 and an extra hydrogen bond with Tyr341 in COX-2 increased the residence time of ligands in the active site in 2-sulfonylalkyl and 2-alkylthio analogs, respectively. [Copyright &y& Elsevier]

Abstract: AgNO3 facilitated the intramolecular ring closure of o-(1-alkynyl)benzenesulfonamides via a regioselective C–N bond forming reaction leading to the formation of 3-substituted benzothiazine derivatives. A number of compounds were prepared in good yields by using this inexpensive and safe methodology. All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties in vitro. A number of compounds that do not contain an enolic hydroxyl group showed selectivities toward COX-2 over COX-1 inhibition. This was further supported by the predictive binding mode of two compounds with COX-1 and -2 proteins through molecular docking studies. [Copyright &y& Elsevier]

Abstract: A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives were synthesized via converting the readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and then reacting with different substituted amines. The molecular structures of two representative compounds, that is, 3 and 5l were confirmed by single crystal X-ray diffraction study. All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties in vitro. The compound 5i showed balanced selectivity towards COX-2 over COX-1 inhibition and good docking scores when docked into the COX-2 protein. [Copyright &y& Elsevier]

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms. [ABSTRACT FROM AUTHOR]

A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N′-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1–S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH2 of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor. [ABSTRACT FROM AUTHOR]